DK3055325T3 - New derivative of an insulin analogue - Google Patents
New derivative of an insulin analogue Download PDFInfo
- Publication number
- DK3055325T3 DK3055325T3 DK14780512.1T DK14780512T DK3055325T3 DK 3055325 T3 DK3055325 T3 DK 3055325T3 DK 14780512 T DK14780512 T DK 14780512T DK 3055325 T3 DK3055325 T3 DK 3055325T3
- Authority
- DK
- Denmark
- Prior art keywords
- insulin
- compound
- ethoxy
- hexamer
- day
- Prior art date
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- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical class N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 title description 217
- 239000004026 insulin derivative Substances 0.000 title description 16
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical class C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 abstract description 36
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- 229920000669 heparin Polymers 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/62—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Endocrinology (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Toxicology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Emergency Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP13187626 | 2013-10-07 | ||
| PCT/EP2014/071236 WO2015052088A1 (en) | 2013-10-07 | 2014-10-03 | Novel derivative of an insulin analogue |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DK3055325T3 true DK3055325T3 (en) | 2018-04-16 |
Family
ID=49301382
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK14780512.1T DK3055325T3 (en) | 2013-10-07 | 2014-10-03 | New derivative of an insulin analogue |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US9896496B2 (sr) |
| EP (1) | EP3055325B1 (sr) |
| JP (1) | JP6499184B2 (sr) |
| KR (1) | KR20160065126A (sr) |
| CN (1) | CN105636979B (sr) |
| AU (1) | AU2014333979B2 (sr) |
| BR (1) | BR112016007166A2 (sr) |
| CA (1) | CA2926701A1 (sr) |
| DK (1) | DK3055325T3 (sr) |
| ES (1) | ES2676065T3 (sr) |
| HR (1) | HRP20180468T1 (sr) |
| HU (1) | HUE036702T2 (sr) |
| IL (1) | IL244507B (sr) |
| MX (1) | MX366636B (sr) |
| PL (1) | PL3055325T3 (sr) |
| PT (1) | PT3055325T (sr) |
| RS (1) | RS57004B1 (sr) |
| RU (1) | RU2673185C2 (sr) |
| SA (1) | SA516370893B1 (sr) |
| SI (1) | SI3055325T1 (sr) |
| WO (1) | WO2015052088A1 (sr) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2910569B1 (en) | 2008-03-18 | 2016-10-05 | Novo Nordisk A/S | Protease stabilized, acylated insulin analogues |
| AR105616A1 (es) | 2015-05-07 | 2017-10-25 | Lilly Co Eli | Proteínas de fusión |
| WO2018083335A1 (en) | 2016-11-07 | 2018-05-11 | Novo Nordisk A/S | Dchbs-active esters of peg compounds and their use |
| JP6690062B2 (ja) * | 2016-12-16 | 2020-04-28 | ノヴォ ノルディスク アー／エス | インスリン含有医薬組成物 |
| JP7377195B2 (ja) | 2017-09-29 | 2023-11-09 | ハンミ ファーマシューティカル カンパニー リミテッド | リンカーとして非ペプチド性重合体結合脂肪酸誘導体化合物を含むタンパク質結合体及びその製造方法 |
| CN111909255A (zh) * | 2019-05-10 | 2020-11-10 | 宁波鲲鹏生物科技有限公司 | 胰岛素衍生物及其制备方法 |
| WO2022017309A1 (zh) | 2020-07-24 | 2022-01-27 | 江苏晟斯生物制药有限公司 | 胰岛素-Fc融合蛋白及其应用 |
| JP2024521757A (ja) * | 2021-05-24 | 2024-06-04 | サンシャイン・レイク・ファーマ・カンパニー・リミテッド | 新規なアシル化インスリンアナログ |
Family Cites Families (134)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2832685A (en) | 1952-05-24 | 1958-04-29 | Crest Foods Co Inc | Solubilization of milk proteins |
| US3528960A (en) | 1968-10-07 | 1970-09-15 | Lilly Co Eli | N-carboxyaroyl insulins |
| US3719655A (en) | 1969-12-05 | 1973-03-06 | Lilly Co Eli | Process for the crystallization of the ammonium and alkali metal salts in insulin |
| US3869437A (en) | 1970-05-08 | 1975-03-04 | Nat Res Dev | Mono-, di, and N{HD A1{B , N{HU B1{B , N{HU B29{B -tri-acylated insulin |
| US3950517A (en) | 1970-05-08 | 1976-04-13 | National Research Development Corporation | Insulin derivatives |
| US4179337A (en) | 1973-07-20 | 1979-12-18 | Davis Frank F | Non-immunogenic polypeptides |
| US4033941A (en) | 1975-12-17 | 1977-07-05 | Eli Lilly And Company | Process for purifying glucagon |
| GB1492997A (en) | 1976-07-21 | 1977-11-23 | Nat Res Dev | Insulin derivatives |
| JPS5767548A (en) | 1980-10-14 | 1982-04-24 | Shionogi & Co Ltd | Insulin analog and its preparation |
| PH25772A (en) | 1985-08-30 | 1991-10-18 | Novo Industri As | Insulin analogues, process for their preparation |
| PH23446A (en) | 1986-10-20 | 1989-08-07 | Novo Industri As | Peptide preparations |
| JPH01254699A (ja) | 1988-04-05 | 1989-10-11 | Kodama Kk | インスリン誘導体及びその用途 |
| DK257988D0 (da) | 1988-05-11 | 1988-05-11 | Novo Industri As | Nye peptider |
| KR900701842A (ko) | 1988-07-20 | 1990-12-04 | 헨리 브뢰늄 | 인간 인슐린 동족체와 그를 포함하는 제제 |
| US5225323A (en) | 1988-11-21 | 1993-07-06 | Baylor College Of Medicine | Human high-affinity neurotransmitter uptake system |
| US5716927A (en) | 1988-12-23 | 1998-02-10 | Novo Nordisk A/S | Insulin analogs having a modified B-chain |
| KR910700262A (ko) | 1988-12-23 | 1991-03-14 | 안네 제케르 | 사람 인슐린 유사체 |
| DE3844211A1 (de) | 1988-12-29 | 1990-07-05 | Hoechst Ag | Neue insulinderivate, verfahren zu deren herstellung, ihre verwendung und eine sie enthaltende pharmazeutische zubereitung |
| ATE120762T1 (de) | 1989-04-20 | 1995-04-15 | Sinai School Medicine | Hepatospezifische insulin-analoga. |
| CA1340994C (en) | 1989-09-21 | 2000-05-16 | Rudolf Edgar Dr. Falk | Treatment of conditions and disease |
| KR930001305B1 (ko) | 1989-10-19 | 1993-02-25 | 니뽕 유우시 가부시끼가이샤 | 당 응답형 고분자 복합체(Polymer Complexes of Sugar Response Type) |
| US5179189A (en) | 1990-01-19 | 1993-01-12 | Nova Pharmaceutical Corporation | Fatty acid terminated polyanhydrides |
| DK45590D0 (sr) | 1990-02-21 | 1990-02-21 | Novo Nordisk As | |
| DK155690D0 (da) | 1990-06-28 | 1990-06-28 | Novo Nordisk As | Nye peptider |
| DK158390D0 (da) | 1990-07-02 | 1990-07-02 | Novo Nordisk As | Nye peptider |
| AU8091091A (en) | 1990-07-26 | 1992-02-18 | University Of Iowa Research Foundation, The | Novel drug delivery systems for proteins and peptides using albumin as a carrier molecule |
| DK10191D0 (da) | 1991-01-22 | 1991-01-22 | Novo Nordisk As | Hidtil ukendte peptider |
| US5336782A (en) | 1991-04-24 | 1994-08-09 | Kuraray Co., Ltd. | Long chain carboxylic acid imide ester |
| EP0952855B1 (en) | 1991-07-03 | 2005-07-27 | Meditech Research Limited | Use of hyaluronan in gene therapy |
| US5268453A (en) | 1991-08-08 | 1993-12-07 | Scios Inc. | Tissue-selective insulin analogs |
| ZA928916B (en) | 1991-11-26 | 1994-05-18 | Lilly Co Eli | Tri-arginine insulins |
| WO1994008599A1 (en) | 1992-10-14 | 1994-04-28 | The Regents Of The University Of Colorado | Ion-pairing of drugs for improved efficacy and delivery |
| US5359030A (en) | 1993-05-10 | 1994-10-25 | Protein Delivery, Inc. | Conjugation-stabilized polypeptide compositions, therapeutic delivery and diagnostic formulations comprising same, and method of making and using the same |
| US5506203C1 (en) | 1993-06-24 | 2001-02-06 | Astra Ab | Systemic administration of a therapeutic preparation |
| UA45321C2 (uk) * | 1993-09-17 | 2002-04-15 | Ново Нордіск А/С | Похідне інсуліну, фармацевтична композиція для лікування діабету та спосіб лікування діабету |
| US6869930B1 (en) | 1993-09-17 | 2005-03-22 | Novo Nordisk A/S | Acylated insulin |
| GB9323588D0 (en) | 1993-11-16 | 1994-01-05 | Cortecs Ltd | Hydrophobic preparation |
| ES2218543T3 (es) | 1994-03-07 | 2004-11-16 | Nektar Therapeutics | Procedimiento y preparacion para la administracion de insulina por via pulmonar. |
| US6500645B1 (en) | 1994-06-17 | 2002-12-31 | Novo Nordisk A/S | N-terminally extended proteins expressed in yeast |
| US5693609A (en) | 1994-11-17 | 1997-12-02 | Eli Lilly And Company | Acylated insulin analogs |
| US5646242A (en) | 1994-11-17 | 1997-07-08 | Eli Lilly And Company | Selective acylation of epsilon-amino groups |
| US6251856B1 (en) | 1995-03-17 | 2001-06-26 | Novo Nordisk A/S | Insulin derivatives |
| EP0871665B1 (en) | 1995-03-17 | 2003-07-23 | Novo Nordisk A/S | Insulin derivatives |
| US5824638A (en) | 1995-05-22 | 1998-10-20 | Shire Laboratories, Inc. | Oral insulin delivery |
| US20030104981A1 (en) | 1995-11-03 | 2003-06-05 | Jelena Mandic | Human insulin analogues |
| US6451970B1 (en) | 1996-02-21 | 2002-09-17 | Novo Nordisk A/S | Peptide derivatives |
| AU3255397A (en) | 1996-07-05 | 1998-02-02 | Novo Nordisk A/S | Method for the production of precursors of insulin, precursors of insulin analogues, and insulin like peptides |
| PT938502E (pt) | 1996-07-11 | 2005-02-28 | Novo Nordisk As | Metodo selectivo por acilacao |
| ATE264871T1 (de) | 1996-07-26 | 2004-05-15 | Aventis Pharma Gmbh | Insulinderivate mit erhöhter zinkbindung |
| US5898067A (en) | 1997-02-07 | 1999-04-27 | Novo Nordisk A/S | Crystallization of proteins |
| US6310038B1 (en) | 1997-03-20 | 2001-10-30 | Novo Nordisk A/S | Pulmonary insulin crystals |
| EP1025125B1 (en) | 1997-10-24 | 2003-06-25 | Novo Nordisk A/S | Aggregates of human insulin derivatives |
| KR20010024556A (ko) | 1997-10-24 | 2001-03-26 | 피터 지. 스트링거 | 불용성 인슐린 조성물 |
| ZA989744B (en) | 1997-10-31 | 2000-04-26 | Lilly Co Eli | Method for administering acylated insulin. |
| ES2230727T3 (es) | 1997-11-12 | 2005-05-01 | Alza Corporation | Procedimiento de administracion dermal de polipeptidos. |
| US6531448B1 (en) | 1997-12-23 | 2003-03-11 | Eli Lilly And Company | Insoluble compositions for controlling blood glucose |
| CA2334859A1 (en) | 1998-06-12 | 1999-12-23 | Kings College London | Insulin analogue |
| GB9814172D0 (en) | 1998-06-30 | 1998-08-26 | Andaris Ltd | Formulation for inhalation |
| CA2341624C (en) | 1998-08-25 | 2008-12-02 | Advanced Inhalation Research, Inc. | Stable spray-dried protein formulations |
| TW570805B (en) | 1998-09-01 | 2004-01-11 | Hoffmann La Roche | Water-soluble pharmaceutical composition in an ionic complex |
| US7030083B2 (en) | 1998-09-09 | 2006-04-18 | University Of Washington | Treatment of eclampsia and preeclampsia |
| KR100617286B1 (ko) | 1998-10-16 | 2006-08-30 | 노보 노르디스크 에이/에스 | 폐 송달을 위한 안정한 농축 인슐린 조제물 |
| US6660715B2 (en) | 1998-11-19 | 2003-12-09 | Massachusetts Institute Of Technology | Nonaqueous solutions and suspensions of macromolecules for pulmonary delivery |
| ATE220917T1 (de) | 1999-01-26 | 2002-08-15 | Lilly Co Eli | Monodisperse formulierungen, die hexamere acylierte insulinanaloge enthalten |
| WO2000061178A1 (en) | 1999-04-13 | 2000-10-19 | Inhale Therapeutics Systems, Inc. | Pulmonary administration of dry powder formulations for treating infertility |
| CA2370302A1 (en) | 1999-04-27 | 2000-11-02 | Benjamin Lee Hughes | Insulin crystals for pulmonary administration |
| US6746853B1 (en) | 1999-05-19 | 2004-06-08 | Xencor, Inc. | Proteins with insulin-like activity useful in the treatment of diabetes |
| JP2003518917A (ja) | 1999-05-19 | 2003-06-17 | ゼンコー | 糖尿病の処置に有用なインシュリン様活性を有する新規タンパク質 |
| US6309633B1 (en) | 1999-06-19 | 2001-10-30 | Nobex Corporation | Amphiphilic drug-oligomer conjugates with hydroyzable lipophile components and methods for making and using the same |
| CN1141974C (zh) | 2000-06-07 | 2004-03-17 | 张昊 | 结肠定位释放的口服生物制剂 |
| US6867183B2 (en) | 2001-02-15 | 2005-03-15 | Nobex Corporation | Pharmaceutical compositions of insulin drug-oligomer conjugates and methods of treating diseases therewith |
| CN1160122C (zh) | 2001-04-20 | 2004-08-04 | 清华大学 | 一种制备口服胰岛素油相制剂的方法 |
| SK15532003A3 (sk) | 2001-05-21 | 2004-06-08 | Nektar Therapeutics | Prípravok inzulínu na pľúcne podávanie |
| US6828297B2 (en) | 2001-06-04 | 2004-12-07 | Nobex Corporation | Mixtures of insulin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
| US6858580B2 (en) | 2001-06-04 | 2005-02-22 | Nobex Corporation | Mixtures of drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
| EP1423136A4 (en) | 2001-08-10 | 2007-07-25 | Epix Pharm Inc | POLYPEPTIDE CONJUGATES HAVING INCREASED CIRCULATION HALF-VIES |
| US6770625B2 (en) | 2001-09-07 | 2004-08-03 | Nobex Corporation | Pharmaceutical compositions of calcitonin drug-oligomer conjugates and methods of treating diseases therewith |
| US7030082B2 (en) | 2001-09-07 | 2006-04-18 | Nobex Corporation | Pharmaceutical compositions of drug-oligomer conjugates and methods of treating disease therewith |
| EP1430082B1 (en) | 2001-09-07 | 2009-10-28 | Biocon Limited | Methods of synthesizing insulin polypeptide-oligomer conjugates, and proinsulin polypeptide-oligomer conjugates and methods of synthesizing same |
| EP1453860A2 (en) | 2001-12-02 | 2004-09-08 | Novo Nordisk A/S | Novel glucose-dependant insulins |
| US8535650B2 (en) | 2001-12-03 | 2013-09-17 | Soligenix, Inc. | Stabilized reverse micelle compositions and uses thereof |
| WO2003050276A1 (en) | 2001-12-05 | 2003-06-19 | Dow Global Technologies Inc. | Method for immobilizing a biologic in a polyurethane-hydrogel composition, a composition prepared from the method, and biomedical applications |
| IL161848A0 (en) | 2001-12-20 | 2005-11-20 | Lilly Co Eli | Insulin moldecule having protracted time action |
| WO2003094956A1 (en) | 2002-05-07 | 2003-11-20 | Novo Nordisk A/S | Soluble formulations comprising monomeric insulin and acylated insulin |
| EP1506003A1 (en) | 2002-05-07 | 2005-02-16 | Novo Nordisk A/S | Soluble formulations comprising insulin aspart and insulin detemir |
| US7601688B2 (en) | 2002-06-13 | 2009-10-13 | Biocon Limited | Methods of reducing hypoglycemic episodes in the treatment of diabetes mellitus |
| CN1165549C (zh) | 2002-06-15 | 2004-09-08 | 江苏万邦生化医药股份有限公司 | 胰岛素的纯化方法 |
| WO2004105790A1 (en) | 2003-06-03 | 2004-12-09 | Novo Nordisk A/S | Stabilized pharmaceutical peptide compositions |
| EP1644411A2 (en) | 2003-07-11 | 2006-04-12 | Novo Nordisk A/S | Stabilised insulin compositions |
| EP1648933B1 (en) | 2003-07-25 | 2009-06-17 | ConjuChem Biotechnologies Inc. | Long lasting insulin derivatives and methods thereof |
| PL2107069T3 (pl) | 2003-08-05 | 2013-06-28 | Novo Nordisk As | Nowe pochodne insuliny |
| AU2004264958B2 (en) | 2003-08-13 | 2010-04-15 | Biocon, Ltd | Micro-particle fatty acid salt solid dosage formulations for therapeutic agents |
| BRPI0414539B8 (pt) * | 2003-09-19 | 2021-05-25 | Novo Nordisk As | composto, composição farmacêutica, e, uso de um composto |
| EP1687428A1 (en) | 2003-11-14 | 2006-08-09 | Novo Nordisk A/S | Processes for making acylated insulin |
| MXPA06005581A (es) | 2003-11-20 | 2006-08-11 | Novo Nordisk As | Formulaciones de peptidos que contienen propilenglicol que son optimas para la produccion y uso en dispositivos de inyeccion. |
| US7371381B2 (en) | 2003-12-12 | 2008-05-13 | Amgen Inc. | Anti-galanin antibodies and uses thereof |
| DE10358387A1 (de) | 2003-12-13 | 2005-07-07 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pulver enthaltend niedermolekulares Dextran und Verfahren zu deren Herstellung |
| US7625865B2 (en) | 2004-03-26 | 2009-12-01 | Universita Degli Studi Di Parma | Insulin highly respirable microparticles |
| AU2005247369A1 (en) | 2004-05-10 | 2005-12-08 | Mdrna, Inc. | Compositions and methods for enhanced mucosal delivery of parathyroid hormone |
| CA2580313C (en) | 2004-07-19 | 2016-03-15 | Biocon Limited | Insulin-oligomer conjugates, formulations and uses thereof |
| DK1791542T3 (en) | 2004-08-23 | 2015-06-15 | Mannkind Corp | Diketopiperazinsalte for pharmaceutical delivery |
| ES2540754T3 (es) | 2004-12-03 | 2015-07-13 | Rhode Island Hospital | Diagnóstico y tratamiento de la Enfermedad de Alzheimer |
| WO2006079641A2 (en) | 2005-01-27 | 2006-08-03 | Novo Nordisk A/S | Insulin derivatives conjugated with structurally well defined branched polymers |
| EP1846446B1 (en) | 2005-02-02 | 2013-06-26 | Novo Nordisk A/S | Insulin derivatives |
| ES2490243T3 (es) | 2005-02-02 | 2014-09-03 | Novo Nordisk A/S | Derivados de insulina |
| US20100216690A1 (en) | 2005-03-18 | 2010-08-26 | Novo Nordisk A/S | Pegylated Single-Chain Insulin |
| WO2007006320A1 (en) | 2005-07-12 | 2007-01-18 | Sherine Hassan Abbas Helmy | Drinkable oral insulin liquid and capsules |
| WO2007041481A1 (en) | 2005-09-29 | 2007-04-12 | Biodel, Inc. | Rapid acting and prolonged acting insulin preparations |
| JP4710533B2 (ja) | 2005-10-07 | 2011-06-29 | 株式会社豊田自動織機 | 牽引車両のドローバー装置 |
| CA2626357A1 (en) | 2005-10-20 | 2007-04-26 | Nastech Pharmaceutical Company Inc. | Intranasal administration of rapid acting insulin |
| DK1969004T3 (da) | 2005-12-28 | 2011-11-28 | Novo Nordisk As | Insulinsammensætninger og metode til at lave en sammensætning |
| US8343914B2 (en) | 2006-01-06 | 2013-01-01 | Case Western Reserve University | Fibrillation resistant proteins |
| EP1991575A1 (en) | 2006-02-21 | 2008-11-19 | Novo Nordisk A/S | Single-chain insulin analogues and pharmaceutical formulations thereof |
| US8722620B2 (en) | 2006-02-27 | 2014-05-13 | Novo Nordisk A/S | Insulin derivatives |
| US20090069215A1 (en) | 2006-03-13 | 2009-03-12 | Novo Nordisk A/S | Acylated Single Chain Insulin |
| ES2548393T3 (es) | 2006-05-09 | 2015-10-16 | Novo Nordisk A/S | Derivado de insulina |
| JP5269766B2 (ja) * | 2006-05-09 | 2013-08-21 | ノボ・ノルデイスク・エー／エス | インスリン誘導体 |
| ES2542146T3 (es) | 2006-07-31 | 2015-07-31 | Novo Nordisk A/S | Insulinas extendidas PEGiladas. |
| KR101699370B1 (ko) | 2006-09-22 | 2017-02-14 | 노보 노르디스크 에이/에스 | 프로테아제 내성 인슐린 유사체 |
| EP2152243A2 (en) | 2007-04-30 | 2010-02-17 | Novo Nordisk A/S | Highly concentrated insulin solutions and compositions |
| EP2514407A1 (en) | 2007-06-01 | 2012-10-24 | Novo Nordisk A/S | Stable non-aqueous pharmaceutical compositions |
| WO2008152106A1 (en) * | 2007-06-13 | 2008-12-18 | Novo Nordisk A/S | Pharmaceutical formulation comprising an insulin derivative |
| CN101743252A (zh) | 2007-07-16 | 2010-06-16 | 诺沃-诺迪斯克有限公司 | 蛋白酶稳定化的、peg化的胰岛素类似物 |
| KR20100053561A (ko) | 2007-08-15 | 2010-05-20 | 노보 노르디스크 에이/에스 | 아실 및 알킬렌 글리콜 부분을 갖는 인슐린 유사체 |
| EP2178910B1 (en) | 2007-08-15 | 2014-10-08 | Novo Nordisk A/S | Insulins with an acyl moiety comprising repeating units of alkylene glycol containing amino acids |
| WO2009060071A1 (en) * | 2007-11-08 | 2009-05-14 | Novo Nordisk A/S | Insulin derivative |
| JP5762001B2 (ja) | 2008-03-14 | 2015-08-12 | ノボ・ノルデイスク・エー／エス | プロテアーゼ安定化インスリンアナログ |
| EP2910569B1 (en) | 2008-03-18 | 2016-10-05 | Novo Nordisk A/S | Protease stabilized, acylated insulin analogues |
| AU2009309623B9 (en) * | 2008-10-30 | 2014-10-02 | Novo Nordisk A/S | Treating diabetes melitus using insulin injections with less than daily injection frequency |
| JP6249773B2 (ja) * | 2010-05-10 | 2017-12-20 | ノヴォ ノルディスク アー／エス | インスリン−亜鉛錯体の調製方法 |
| JP5931857B2 (ja) | 2010-06-23 | 2016-06-08 | ノヴォ ノルディスク アー／エス | 追加のジスルフィド結合を含有するインスリン誘導体 |
| EP2585484A1 (en) | 2010-06-23 | 2013-05-01 | Novo Nordisk A/S | Insulin analogues containing additional disulfide bonds |
| CA2815419A1 (en) * | 2010-10-27 | 2012-05-03 | Novo Nordisk A/S | Treating diabetes melitus using insulin injections administered with varying injection intervals |
| JP6199956B2 (ja) | 2012-04-11 | 2017-09-20 | ノヴォ ノルディスク アー／エス | インスリン製剤 |
-
2014
- 2014-10-03 BR BR112016007166A patent/BR112016007166A2/pt not_active IP Right Cessation
- 2014-10-03 DK DK14780512.1T patent/DK3055325T3/en active
- 2014-10-03 HU HUE14780512A patent/HUE036702T2/hu unknown
- 2014-10-03 ES ES14780512.1T patent/ES2676065T3/es active Active
- 2014-10-03 RU RU2016114098A patent/RU2673185C2/ru not_active IP Right Cessation
- 2014-10-03 KR KR1020167010201A patent/KR20160065126A/ko not_active Application Discontinuation
- 2014-10-03 PL PL14780512T patent/PL3055325T3/pl unknown
- 2014-10-03 WO PCT/EP2014/071236 patent/WO2015052088A1/en active Application Filing
- 2014-10-03 RS RS20180322A patent/RS57004B1/sr unknown
- 2014-10-03 US US15/023,872 patent/US9896496B2/en not_active Expired - Fee Related
- 2014-10-03 AU AU2014333979A patent/AU2014333979B2/en not_active Ceased
- 2014-10-03 PT PT147805121T patent/PT3055325T/pt unknown
- 2014-10-03 EP EP14780512.1A patent/EP3055325B1/en not_active Not-in-force
- 2014-10-03 CN CN201480055375.6A patent/CN105636979B/zh not_active Expired - Fee Related
- 2014-10-03 MX MX2016004325A patent/MX366636B/es active IP Right Grant
- 2014-10-03 JP JP2016546167A patent/JP6499184B2/ja not_active Expired - Fee Related
- 2014-10-03 SI SI201430644T patent/SI3055325T1/en unknown
- 2014-10-03 CA CA2926701A patent/CA2926701A1/en not_active Withdrawn
-
2016
- 2016-03-08 IL IL244507A patent/IL244507B/en not_active IP Right Cessation
- 2016-04-07 SA SA516370893A patent/SA516370893B1/ar unknown
-
2018
- 2018-03-20 HR HRP20180468TT patent/HRP20180468T1/hr unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CA2926701A1 (en) | 2015-04-16 |
| US9896496B2 (en) | 2018-02-20 |
| ES2676065T3 (es) | 2018-07-16 |
| AU2014333979B2 (en) | 2018-02-15 |
| BR112016007166A2 (pt) | 2017-09-12 |
| IL244507B (en) | 2018-05-31 |
| IL244507A0 (en) | 2016-04-21 |
| HRP20180468T1 (hr) | 2018-05-04 |
| EP3055325B1 (en) | 2018-01-03 |
| PT3055325T (pt) | 2018-04-06 |
| CN105636979B (zh) | 2020-01-10 |
| RS57004B1 (sr) | 2018-05-31 |
| RU2673185C2 (ru) | 2018-11-22 |
| CN105636979A (zh) | 2016-06-01 |
| SA516370893B1 (ar) | 2018-08-13 |
| WO2015052088A1 (en) | 2015-04-16 |
| RU2016114098A3 (sr) | 2018-05-21 |
| AU2014333979A1 (en) | 2016-03-24 |
| US20160215037A1 (en) | 2016-07-28 |
| HUE036702T2 (hu) | 2018-07-30 |
| MX2016004325A (es) | 2016-07-11 |
| MX366636B (es) | 2019-07-17 |
| PL3055325T3 (pl) | 2018-06-29 |
| RU2016114098A (ru) | 2017-11-15 |
| EP3055325A1 (en) | 2016-08-17 |
| JP2017502074A (ja) | 2017-01-19 |
| KR20160065126A (ko) | 2016-06-08 |
| SI3055325T1 (en) | 2018-05-31 |
| JP6499184B2 (ja) | 2019-04-10 |
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